Agents that stimulate therapeutic angiogenesis and techniques and devices that enable their delivery

ABSTRACT

A method including positioning a catheter at a location in a blood vessel; imaging a thickness of a portion of a wall of the blood vessel at the location; identifying a treatment site; advancing a needle a distance into the wall of the blood vessel to the treatment site; and introducing a treatment agent through the needle to the treatment site. A composition including an inflammation-inducing agent and a carrier in the form of microspheres having a particle size suitable for transvascular delivery. A composition including a therapeutic angiogenesis promoter in a carrier and an opsonin-inhibitor coupled to the carrier. An apparatus for delivery of a therapeutic angiogenesis promoter.

This application is a divisional application of U.S. patent applicationNo. 10/011,071, filed Nov. 30, 2001, now U.S. Pat. No. 6,702,744. Thisapplication also claims the benefit of the earlier filing date ofProvisional Application Ser. No. 60/300,042, filed Jun. 20, 2001, byEvgenia Mandrusov, Murthy V. Simhambhatla, Syed Hossainy, Gene Michal,Chuck Claude, and Jessica G. Chiu, titled “Angiogenesis/ArteriogenesisTreatment Agents and Technique and Device for Locating TreatmentAgents,” all incorporated herein by reference.

BACKGROUND

1. Field

This invention relates to resolving ischemia by inducing formation ofblood vessels through therapeutic angiogenesis.

2. Relevant Art

A major component of morbidity and mortality attributable tocardiovascular disease occurs as a consequence of the partial orcomplete blockage of vessels carrying blood in the coronary and/orperipheral vasculature. When such vessels are partially occluded, lackof blood flow causes ischemia to the muscle tissues supplied by suchvessel, consequently inhibiting muscle contraction and proper function.Total occlusion of blood flow causes necrosis of the muscle tissue.

Blood vessel occlusions are commonly treated by mechanically enhancingblood flow in the affected vessels. Such mechanical enhancements areoften provided by employing surgical techniques that attach natural orsynthetic conduits proximal and distal to the areas of occlusion,thereby providing bypass grafts, or revascularization by various meansto physically enlarge the vascular lumen at the site of occlusion. Theserevascularization procedures involve such devices as balloons,endovascular knives (atherectomy), and endovascular drills. The surgicalapproach is accompanied by significant morbidity and even mortality,while the angioplasty-type processes are complicated by recurrentstenoses in many cases.

In some individuals, blood vessel occlusion is partially compensated bynatural processes, in which new vessels are formed (termed“angiogenesis”) and small vessels are enlarged (termed “arteriogenesis”)to replace the function of the impaired vessels. These new conduits mayfacilitate restoration of blood flow to the deprived tissue, therebyconstituting “natural bypasses” around the occluded vessels. However,some individuals are unable to generate sufficient collateral vessels toadequately compensate for the diminished blood flow caused bycardiovascular disease. Accordingly, it would be desirable to provide amethod and apparatus for delivering agents to help stimulate the naturalprocess of therapeutic angiogenesis to compensate for blood loss due toan occlusion in a coronary and peripheral arteries in order to treatischemia.

SUMMARY

A method is disclosed. In one embodiment the method includes positioninga delivery device such as a catheter at a location in a blood vessel andadvancing the delivery device a distance into a wall of the blood vesselto a treatment site. A treatment agent is then introduced through thedelivery device to the treatment site. The method also includesidentifying a treatment site based on imaging a thickness of a portionof the wall of the blood vessel. In the example of introducing atreatment agent that would stimulate a therapeutic angiogenesisresponse, the method describes a technique for accurately delivering atreatment agent into the wall of the blood vessel or beyond the wall ofthe blood vessel as the particular situation may dictate. The methodutilizes imaging of a thickness of the wall of a blood vessel toaccurately place the treatment agent. Suitable imaging techniquesinclude, but are not limited to, ultrasonic imaging, optical imaging,and magnetic resonance imaging.

In another embodiment, a method includes introducing a treatment agentin a sustained release composition or carrier. Treatment agents that cansustain their effectiveness for a period of up to one to ten weeks,preferably two to eight weeks, offer maximum benefit for the stimulationof therapeutic angiogenesis. Methods of inducing coronary or peripheraltherapeutic angiogenesis by local delivery of sustained releasetreatment agents using percutaneous devices are described. Such devicesmay be intraventricular (coronary) or intravascular (coronary andperipheral).

In another embodiment, a method includes placing a treatment agent in oraround a blood vessel or other tissue that stimulates therapeuticangiogenesis by inducing an inflammation response in tissue.

In still another embodiment, a sustained-release composition comprisinga treatment agent in a form suitable for transvascular delivery isdescribed. Also, a composition comprising a carrier including atreatment agent and an opsonin-inhibitor coupled to the carrier.

In a further embodiment, an apparatus is described that allows theaccurate introduction of a treatment agent in or around a blood vessel.The apparatus includes, for example, a catheter body capable oftraversing a blood vessel and a dilatable balloon assembly coupled tothe catheter body comprising a balloon having a proximal wall. A needlebody is disposed within the catheter body and comprises a lumen havingdimensions suitable for a needle to be advanced there through. Theneedle body includes an end coupled to the proximal wall of the balloon.The apparatus also includes an imaging body disposed within the catheterbody and comprising a lumen having a dimension suitable for a portion ofan imaging device to be advanced there through. The apparatus furtherincludes a portion of an imaging device disposed within the imaging bodyadapted to generate imaging signals of the blood vessel, includingimaging signals of a thickness of the wall of a blood vessel. Anapparatus such as described is suitable for accurately introducing atreatment agent at a desired treatment site in or around a blood vessel.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 schematically illustrates a perspective and cross-section view ofa blood vessel:

FIG. 2 schematically illustrates a planar cross-sectional view ofcomponents of a coronary artery network;

FIG. 3 is a simplified cross-sectional view of an embodiment of asubstance delivery apparatus in the form of a catheter assembly having aballoon and a therapeutic substance delivery assembly;

FIG. 4 schematically illustrates a planar cross-section of the substancedelivery apparatus of FIG. 3 through line A-A′;

FIG. 5 schematically illustrates a planar cross-section of the substancedelivery apparatus of FIG. 3 through line B-B′;

FIG. 6 schematically illustrates a cross-sectional view of the distalsection of the substance delivery apparatus of FIG. 3 with the balloonin an undeployed configuration;

FIG. 7 schematically illustrates a cross-sectional view of the distalsection of the substance delivery apparatus of FIG. 3 with the balloonin a deployed configuration;

FIG. 8 schematically illustrates an optical imaging system for use in asubstance delivery apparatus such as a catheter assembly;

FIG. 9 schematically illustrates a cross-sectional side view ofcomponents of an alternative catheter assembly including an opticalimaging system.

FIG. 10 schematically illustrates the left coronary artery networkhaving a catheter assembly introduced therein; and

FIG. 11 presents a block diagram for introducing a treatment agent.

The features of the described embodiments are specifically set forth inthe appended claims. However, the embodiments are best understood byreferring to the following description and accompanying drawings, inwhich similar parts are identified by like reference numerals.

DETAILED DESCRIPTION

In connection with the description of the various embodiments, thefollowing definitions are utilized:

“Therapeutic angiogenesis” refers to the processes of causing orinducing angiogenesis and arteriogenesis.

“Angiogenesis” is the promotion or causation of the formation of newblood vessels in the ischemic region.

“Arteriogenesis” is the enlargement of pre-existing collateral vessels.The collateral vessels allow blood to flow from a well-perfused regionof the vessel into the ischemic region.

“Ischemia” is a condition where oxygen demand of the tissue is not metdue to localized reduction in blood flow caused by narrowing orocclusion of one or more vessels. Narrowing of arteries such as coronaryarteries or their branches, is most often caused by thrombosis or viadeposits of fat, connective tissue, calcification of the walls, orrestenosis due to abnormal migration and proliferation of smooth musclecells.

“Occlusion” is the total or partial obstruction of blood flow through avessel.

“Treatment agent” includes agents directed to specific cellular bindingsites (e.g., receptor binding treatment agents) and agents that induceinflammation.

“Specific binding treatment agent” or “receptor binding treatment agent”includes a protein or small molecule that will induce and/or modulate atherapeutic angiogenic response through interaction with a specificbinding site (e.g., a binding within a cell or on a cell surface).Representative treatment agents include, but are not limited to,vascular endothelial growth factor (VEGF) in any of its multipleisoforms, fibroblast growth factors, monocyte chemoattractant protein 1(MCP-1), transforming growth factor beta (TGF-beta) in any of itsmultiple isoforms, transforming growth factor alpha (TGF-alpha), lipidfactors, hypoxia-inducible factor 1-alpha (HIF-1-alpha), PR39, DEL 1,nicotine, insulin-like growth factors, placental growth factor (PIGF),hepatocyte growth factor (HGF), estrogen, follistatin, proliferin,prostaglandin E1, prostaglandin E2, cytokines, tumor necrosis factor(TNF-alpha), erythropoietin, granulocyte colony-stimulating factor(G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF),angiogenin, hormones, and genes that encode such substances.

“Non-specific treatment agent” includes, as described in more detailherein, various agents that induce inflammation.

“Carrier” includes a matrix that contains one or more treatment agents.A suitable carrier may take the form of a nanoparticle (e.g.,nanosphere) or microparticle (e.g., microsphere) as the situation maydictate.

Referring to FIG. 1, a non-diseased artery is illustrated as arepresentative blood vessel. Artery 100 includes an arterial wall havinga number of layers. Innermost layer 110 is generally referred to as theintimal layer that includes the endothelium, the subendothelial layer,and the internal elastic lamina. Medial layer 120 is concentricallyoutward from intimal layer 110 and bounded by external elastic laminaand adventitial layer 130 is the outermost layer. There is no externalelastic lamina in a vein. Medial layer 120 (in either an artery or vein)primarily consists of smooth muscle fibers and collagen. Beyond mediallayer 120 and adventitial layer 130 lies the extravascular tissueincluding, adjacent adventitial layer 120 (and possibly including aportion of adventitial layer 120), area 140 referred to asperi-adventitial site (space) or area. Areas radially outward from aperi-adventitial space include connective tissue such as adipose tissuethat is most likely located, in terms of areas around the heart, towardthe epicardial surface of the heart and myocardial tissue composed ofmuscle fibers.

FIG. 2 illustrates components of a coronary artery network. In thissimplified example, vasculature 150 includes left anterior descendingartery (LAD) 160, left circumflex artery (LCX) 170 and right coronaryartery (RCA) 180. Sites 190A, 190B, and 190C are preferably in theperi-adventitial space or radially outward from the peri-adventitialspace (e.g., in adipose or myocardial tissue). Occlusion 185 is shown inLCX 170. Occlusion 185 limits the amount of oxygenated blood flowthrough LCX 170 to the myocardium that it supplied, resulting inischemia of this tissue.

To improve the function of the artery network, it is generally desiredto either remove occlusion 185 (for example through an angioplastyprocedure), bypass occlusion 185 or induce therapeutic angiogenesis tomakeup for the constriction and provide blood flow to the ischemicregion (e.g., downstream of occlusion 185). FIG. 2 shows therapeuticangiogenesis induced at sites 190A (associated with LCX 170); 190B(associated with LAD 160); and 190C (associated with RCA 180). Byinducing therapeutic angiogenesis at sites 190A, 190B, and 190C,permanent revascularization of the network is accomplished, thuscompensating for reduced flow through LCX 170. The following paragraphsdescribe compositions, techniques and an apparatus suitable for inducingtherapeutic angiogenesis.

A. Specific Binding Treatment Agents

In one embodiment, therapeutic angiogenesis is induced and modulated bylocally delivering a treatment agent in a sustained-release carrier. Thesustained-release carrier comprising a treatment agent may bestrategically placed, for example, along an occlusion to produce anangiogenic concentration gradient to encourage the specific directionalgrowth or expansion of collateral vessels. For example, in reference toFIG. 2, treatment agents placed at zone 190A, above (as viewed) occludedvessel LCX 170 are selected such that, while up-stream, a therapeuticangiogenic or arteriogenic response will encourage growth of collateralsaround occlusion 185 meeting up with LCX 170 down-stream of theocclusion. Similarly, a treatment agent strategically placed at alocation in a region near to left coronary artery 160 (e.g., region190B) will encourage bridging of collateral vessels, in this case,between left coronary artery 160 and LCX 170. Similar encouragement andbridging may be obtained by strategically placing a treatment agent at aregion of RCA 180 (such as region 190C). While the application oftherapeutic angiogenesis to alleviating ischemia resulting from a flowlimiting obstruction in the LCX is described, those familiar with theart will appreciate that the method described is applicable to thetreatment of flow limiting obstructions in other coronary vessels and inthe peripheral vasculature.

Suitable treatment agents include specific binding or receptor bindingtreatment agents. Suitable sustained-release carriers encapsulating thespecific binding agents may take the form of polymer nanoparticles ormicroparticles, typically in the form of nanospheres or microspheres,having an average particle size less than 100 microns (μm) andpreferably less than about 10 μm to, in one aspect, enable deliverythrough a catheter equipped with an injection needle. Sustained releaseof treatment agents for a period of up to one to ten weeks, preferablyup to two to eight weeks is believed to offer maximum benefit for thestimulation of therapeutic angiogenesis. In another embodiment, thesustained release of treatment agents over a period of one day or longeris preferred. The loading of the receptor binding treatment agent in thesustained release carrier is in the range of about 0.5 percent to about30 percent weight by volume (w/v), and the total dose of the receptorbinding treatment agent delivered to the treatment location is in therange of about 1 microgram (μg) to about 1 gram (g).

Sustained release microparticle formulations with different releaserates may be delivered in combination to achieve multi-modal releaseprofiles over a period of time.

B. Non-Specific Treatment Agents

As stated above, specific binding or receptor binding treatment agentscan induce therapeutic angiogenesis. One embodiment of another suitabletreatment agent that will induce and/or modulate a therapeuticangiogenic response is an inflammation-inducing agent. Studies haveshown that tissue, including blood vessels, respond to injury induced byimplanting foreign materials in three broad phases. The first phase ischaracterized by minimal inflammatory reaction, with the presence of afew lymphocytes, plasma cells, monocytes, and polymorphonuclearleukocytes. The response to injury in this first phase is determinedprimarily by the extent of injury caused, for example, by a needle of aneedle catheter contacting a blood vessel and the volume of therapeuticsubstance (e.g., treatment agent) injected to the site of interest. Thesecond response to injury phase is characterized by a predominance ofmonocytes and macrophages. In the case of biodegradable implants, theduration of this second phase is determined by the rate ofbiodegradation of the carrier. During this phase, monocytesdifferentiate into macrophages at the site of injury and the macrophagesthemselves fuse into foreign body “giant” cells. Fibroblast infiltrationand neoangiogenesis are also observed at this stage. For biodegradableimplants, there is a third response to injury phase, characterized bythe breakdown of the biodegradable material. In this phase, macrophagespredominate at the site of implantation. The extent of inflammation andthe concentration of monocyte/macrophages at the implantation sitereaches a peak at this third phase. Monocyte accumulation and activationis thought to be a potent means of inducing therapeutic angiogensis

In one embodiment, ischemic regions supplied by a blood vessel such asischemic region caused by a lesion in the LCX 170 in FIG. 2 may betreated by implantation of an inflammation-inducing agent (a“non-specific” agent) optionally combined with or contained in(encapsulated) a sustained-release carrier. The implantation may beaccomplished non-invasively through, for example, catheter-basedtechnologies, minimally invasively, or in conjunction with surgicalprocedures. The extent and duration of inflammation is dependent on thenon-specific agent being implanted. A combination of agents may beimplanted to modulate the extent of inflammation over a period of time,which is typically on the order of about two weeks to about eight weeks.

Suitable inflammation-inducing agents include, but are not limited to,(1) bioresorbable inorganic compounds such as sol gel particles andcalcium phosphate glass comprising iron; (2) fibrin, gelatin, lowmolecular weight hyaluronic acid, and chitin; (3) bacterialpolysaccharides; (4) metals; and (5) certain other polymers (whichthemselves may function as both treatment agent and carrier, including asustained-release carrier) including bioresorbable polymers such aspolycaprolactone (PCL), polyhydroxybutyrate-valerate (PHBV),poly(oxy)ethylene (POE), and non-bioresorbable polymers such aspolyurethanes and silicones. The inflammation-inducing treatment agentmay be combined as a composition with one or more other specific bindingor receptor binding treatment agents that are believed to inducetherapeutic angiogenesis such as growth factors.

Representative examples of inflammation-inducing treatment agents thatmay be combined, in one embodiment, with a sustained release carrierinclude the following.

Silica sol gel particles, such as manufactured by Bioxid LTD OY ofTurku, Finland, are bioresorbable inorganic compounds that can bepro-inflammatory on their own and also serve as a drug eluting reservoirfor other pro-inflammatory agents (e.g., lipopolysaccharides (LPS),chitin, etc.). Calcium-phosphate glass containing iron will degrade in ahumid environment as a function of the iron composition, resulting in anabsorbable glass. One example of absorbable glass is made by MOSCI, Inc.of Rolla, Mo. The absorbable glass may induce controlled inflammation bythe physical dimension of the degradation product. A combination of PLGAcoated (with or without activation) or partially coated absorbable glassmay be employed to modulate the degradation rate of different species.

Chitin is a polysaccharide derived principally from crab shells, andshows a pro-inflammatory reaction. Micronized chitin can be incorporatedinto microspheres or disbursed into a polymer system such as describedabove to enhance the inflammatory action of treatment agent ofmicrospheres or precipitated polymers. The micronized chitin can also bedisbursed in a gel that may then be extruded via a needle catheter to adesired treatment location (within the vascular or myocardium). Gelatin(a partially degraded form of collagen) and fibrin may be utilized in asimilar manner.

The outer membranes of gram-negative bacteria containinglipopolysaccharides (LPS) can be pro-inflammatory. Isolation of LPS andincorporation into degradeable microspheres can enhance the inflammatoryreaction of the microspheres and provide a more potent angiogenicaction.

The cell walls of blood vessels are typically rich in glycocalyx andother specific antigens. Systemic immune response may be upregulated byadministration of vaccines or denatured proteins such as Ab, Fb, etc. Inanother embodiment, the localized introduction (e.g., through acatheter) of vaccines or certain denatured proteins may be used incombination with, for example, inflammatory-inducing treatment agents topotentiate the controlled inflammatory effect

Particles of metal such as gold (Au) and titanium (Ti) are known toinduce inflammation and activate monocytes. These particles may beinjected as a suspension at a local site of interest via, for example, aneedle catheter. To amplify an effect, such thermally conductiveparticles can be heated with, for example, using a 900 to 1200 nanometer(nm) range remote source of radio frequency energy to further causecontrolled damage to the tissue resulting in inflammation and promotingtherapeutic angiogenesis; 10 to 100 nanometer (nm) spherical particlesare shown to have this remote activatible heating effect.

C. Methods of Forming Sustained Release Particles

In the previous paragraphs, both specific binding treatment agents andnon-specific binding treatment agents have been described in conjunctionwith promoting therapeutic angiogenesis. Such promotion is encouraged,in one embodiment, by delivering the treatment agent in or with asustained-release carrier. Suitable materials for sustained-releasecarriers include, but are not limited to, encapsulation polymers such aspoly (L-lactide), poly (D,L-lactide), poly (glycolide), poly(lactide-co-glycolide), polycaprolactone, polyanhydride, polydiaxanone,polyorthoester, polyamino acids, or poly (trimethylene carbonate), andcombinations thereof. To form a sustained-release carrier compositionof, for example, microparticles or nanoparticles (e.g., microspheres ornanospheres) comprising one or more treatment agents including anon-specific treatment agent and/or a specific binding agent, thefollowing techniques may be used.

1. Solvent Evaporation

In this method, the polymer is dissolved in a volatile organic solventsuch as methylene chloride. The treatment agent is then added to thepolymer solution either as an aqueous solution containing an emulsifyingagent such as polyvinyl alcohol (PVA), or as a solid dispersion, andstirred, homogenized or sonicated to create a primary emulsion ofprotein in the polymer phase. This emulsion is stirred with an aqueoussolution containing an emulsifying agent such as PVA to create asecondary emulsion of treatment agent containing polymer in the aqueousphase. This emulsion is stirred in excess water, optionally under vacuumto remove the organic solvent and harden the particles. The hardenedparticles are collected by filtration or centrifugation andlyophillized. A desired particle size (e.g., microparticle ornanoparticle) may be selected by varying the preparation conditions(e.g., viscosity of the primary emulsion, concentration of the treatmentagent, mixing (shear) rate, etc.). The particles tend to adopt aspherical shape in response to minimizing surface tension effects.

2. Coacervation:

In this method, a primary emulsion of treatment agent in an aqueousphase is formed as in the solvent evaporation method. This emulsion isthen stirred with a non-solvent for the polymer, such as silicone oil toextract the organic solvent and form embryonic particles of polymer withtrapped treatment agent. The non-solvent is then removed by the additionof a volatile second non-solvent such as heptane, and the particleshardened. The hardened particles are collected by filtration orcentrifugation and lyophillized. Again, the particle size may beselected as described above with reference to solvent evaporation.

3. Spray Drying:

In this method, the treatment agent, formulated as lyophilized powder issuspended in a polymer phase consisting of polymer dissolved in avolatile organic solvent such as methylene chloride. The suspension isthen spray dried to produce polymer particles with entrapped treatmentagent. The particle size may be selected as described above withreference to solvent evaporation.

4. Cryogenic Process:

In this method, the treatment agent, formulated as lyophillized powderis suspended in a polymer phase consisting of polymer dissolved in avolatile organic solvent such as methylene chloride. The suspension issprayed into a container containing frozen ethanol overlaid with liquidnitrogen. The system is then warmed to −70° C. to liquify the ethanoland extract the organic solvent from the treatment agent particles. Thehardened microspheres are collected by filtration or centrifugation andlyophillized.

5. In situ Process:

Sustained release carriers (e.g., microparticles and/or nanoparticles)may be formed before introduction (e.g., injection) into the bloodvessel as described above, or they may be formed in situ. One way toform such particles in situ is by co-desolving a treatment agent and amatrix forming polymer in a water miscible solvent such as dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP), ethanol or glycofural andinjecting the solution at the site of treatment with, for example, acatheter to precipitate out polymer particles. Several polymersolutions, each consisting of a polymer formulation with a differentdegradation rate can be injected in sequence to precipitate out a mixedpopulation of polymer particles, in order to obtain a multi-modalrelease profile.

6. Example of Loading and Dose for Inducing/Modulating TherapeuticAngiogenesis

As noted above, one example of the preparation of nanoparticles (e.g.,nanospheres) or microparticles (e.g., microspheres) suitable for use intherapeutic angiogenesis is in the form of a solution. Nanoparticles ormicroparticles may be loaded with specific or non-specific agents in therange of 0.5-30 percent w/v. In the case of inflammatory agents, loadingmay be as high as 100 percent w/v. A suitable dose may be calculated asfollows:DOSE=number of injections×% suspension of nano- and/ormicroparticles[(weight of nano- and/or microparticles)/volume ofsolution]×volume of solution×% loading[weight of agent/(weight of nano-and/or microparticles)].

Using an inflammatory treatment agent such as gold particles as anexample, loading may be 100 percent. In 0.2 ml solution five percent w/vof particles provides for maximal dose of 10 micrograms of material perinjection. The number of injections is determined by an operator. Thetotal dose is in the range of 1 microgram to 1 gram. It is to beappreciated that the optimal dose may be determined in a relevant animalmodel of ischemia by delivering the nano- and/or microparticlesuspension through a needle catheter or simply by injecting duringopen-heart procedure and generating a dose-response curve.

D. Compositions Having a Particle Size of 10 Microns or Less

Treatment agents, including treatment agents combined with a carrier(e.g., a sustained release carrier), having a particle size greater thanapproximately 10 microns have the potential, when introduced into thearterial vascular system, of being trapped in the capillary bed.Trapping large numbers of microparticles in the capillary bed couldresult in ischemia. Treatment agent compositions having particlediameters less than about 10 microns, however, are rapidly phagocytosed,resulting in reduced availability of the treatment agent at targetsites, where, for example, sustained-released of the treatment agent maybe desired in a certain therapeutic concentration range.

Regarding phagocytosis, when a foreign material is implanted into a hosttissue, the first event to occur at the tissue-material interface is theadsorption of plasma proteins from blood onto the surface of the foreignmaterial. Opsonins are plasma proteins, such as complement andimmunoglobulin, that adhere to foreign materials such as nanoparticlesand facilitate their phagocytosis through the recognition of theadsorbed opsonins by macrophages of the reticulo-endothelial system.Microspheres larger than about 10 microns are also opsonized, but aregenerally considered too large to be phagocytosed.

In one embodiment, the treatment agent compositions suitable fortherapeutic angiogenesis are rendered resistant to phagocytosis byinhibiting opsonin protein adsorption to the composition particles. Inthis regard, treatment agent compositions including sustained releasecarriers comprise particles having an average diameter of up to about 10microns are contemplated.

One method of inhibiting opsonization and subsequent rapid phagocytosisof treatment agents is to form a composition comprising a treatmentagent disposed within a carrier (e.g., a sustained release carrier) andto coat the carrier with an opsonin inhibitor. One suitableopsonin-inhibitor includes polyethylene glycol (PEG) which creates abrush-like steric barrier to opsonization. PEG may alternatively beblended into the polymer constituting the carrier, or incorporated intothe molecular architecture of the polymer constituting the carrier, as acopolymer, to render the carrier resistant to phagocytosis. Examples ofpreparing the opsonin-inhibited microspheres include the following.

For the encapsulation polymers, a blend of a polyalkylene glycol such aspolyethylene glycol (PEG), polypropylene 1,2-glycol or polypropylene1,3-glycol is co-dissolved with an encapsulating polymer in a commonorganic solvent during the carrier forming process. The percentage ofPEG in the PEG/encapsulating polymer blend is between five percent and60 percent by weight. Other hydrophilic polymers such as polyvinylpyrolidone, polyvinyl alchohol, or polyoxyethylene-polyoxypropylenecopolymers can be used in place of polyalkylene glycols, althoughpolyalkylene glycols and more specifically, polyethylene glycol isgenerally preferred.

Alternatively, a diblock or triblock copolymer of an encapsulatingpolymer such as poly (L-lactide), poly (D,L-lactide), or poly(lactide-co-glycolide) with a polyalkylene glycol may be prepared.Diblocks can be prepared by: (i) reacting the encapsulating polymer witha monomethoxy polyakylene glycol such as PEG with one protected hydroxylgroup and one group capable of reacting with the encapsulating polymer,(ii) by polymerizing the encapsulating polymer on to the monomethoxypolyalkylene glycol such as PEG with one protected group and one groupcapable of reacting with the encapsulating polymer; or (iii) by reactingthe encapsulating polymer with a polyalkylene glycol such as PEG withamino functional termination. Triblocks can be prepared as describedabove using branched polyalkylene glycols with protection of groups thatare not to react. Opsonization resistant carriers(microparticles/nanoparticles) can also be prepared using the techniquesdescribed above to form sustained-release carriers(microparticles/nanoparticles) with these copolymers.

A second way to inhibit opsonization is the biomimetic approach. Forexample, the external region of cell membrane, known as the“glycocalyx”, is dominated by glycoslylated molecules which preventnon-specific adhesion of other molecules and cells. Surfactant polymersconsisting of a flexible poly (vinyl amine) backbone randomly-dextranand alkanoyl (hexanoyl or lauroyl) side chains which constrain thepolymer backbone to lie parallel to the substrate. Hydrated dextran sidechains protrude into the aqueous phase, creating a glycocalyx-likemonolayer coating which suppresses plasma protein deposition on theforeign body surface. To mimic glycocalyx, glycocalyx-like molecules canbe coated on the carriers (e.g., nanoparticles or microparticles) orblended into a polymer constituting the carrier to render the treatmentagent resistant to phagocytosis. An alternate biomimetic approach is tocoat the carrier with, or blend in phosphorylcholine, a syntheticmimetic of phosphatidylcholine, into the polymer constituting thecarrier.

For catheter delivery, a carrier comprising a treatment agent (e.g., thecomposition in the form of a nanoparticle or microparticle) may besuspended in a fluid for delivery through the needle, at a concentrationof about one percent to about 20 percent weight by volume. In oneembodiment, the loading of the treatment agent in a carrier is about 0.5percent to about 30 percent by weight of the composition.Co-encapsulated with protein or small molecule angiogen treatment agentscould be stabilizers that prolong the biological half-life of thetreatment agent in the carrier upon injection into tissue. Stabilizersmay also be added to impart stability to the treatment agent duringencapsulation. Hydrophilic polymers such as PEG or biomimetic brush-likedextran structures or phosphorylcholine are either coated on the surfaceor the carrier, grafted on the surface of the carrier, blended into thepolymer constituting the carrier, or incorporated into the moleculararchitecture of the polymer constituting the carrier, so the carrier isresistant to phagocytosis upon injection into the target tissuelocation.

E. Catheter Assembly

One concern of introducing sustained-release treatment agentcompositions into or adjacent blood vessels or the myocardium is thatthe composition remain (at least partially) at the treatment site forthe desired treatment duration (e.g., two to eight weeks). Accordingly,in another embodiment, an apparatus (a catheter assembly) is describedfor accurately locating a treatment agent at a location in a bloodvessel (preferably beyond the media layer) or in a peri-adventitialspace adjacent to a blood vessel, or areas radially outward from aperi-adventitial space, or at tissue location such as the tissue of themyocardium. It is appreciated that a catheter assembly is one techniquefor introducing treatment agents and the following description is notintended to limit the application or placement of the treatment agentcompositions described above.

Referring now to the drawings, wherein similar parts are identified bylike reference numerals, FIGS. 3,4, and 5 illustrate one embodiment of adelivery apparatus. In general, the delivery apparatus provides a systemfor delivering a substance, such as a treatment agent or a combinationof treatment agents optionally presented as a sustained releasecomposition, to or through a desired area of a blood vessel (aphysiological lumen) or tissue in order to treat a localized area of theblood vessel or to treat a localized area of tissue possibly locatedadjacent to the blood vessel. The delivery apparatus is similar incertain respects to the delivery apparatus described in commonly-owned,U.S. patent application Ser. No. 09/746,498 (filed Dec. 21, 2000),titled “Directional Needle Injection Drug Delivery Device”, of Chow, etal., and incorporated herein by reference. The delivery apparatusincludes a catheter assembly 300, which is intended to broadly includeany medical device designed for insertion into a blood vessel orphysiological lumen to permit injection and/or withdrawal of fluids, tomaintain the potency of the lumen, or for any other purpose.

In one embodiment, catheter assembly 300 is defined by elongatedcatheter body (cannula) 312 having proximal end 313 and distal end 314.FIG. 4 shows catheter assembly 300 through line A-A′ of FIG. 3 (atdistal end 314). FIG. 5 shows catheter assembly 300 through line B-B′ ofFIG. 3 (at proximal end 313).

Referring to FIG. 3 and FIG. 4, catheter assembly 300 includes catheterbody 312 extending from proximal end 313 to distal end 314. In thisexample, guidewire lumen 316 is formed within catheter body 312 forallowing catheter assembly 300 to be fed and maneuvered over guidewire318 (shown at this point within guidewire lumen 316).

Balloon 320 is incorporated at distal end 314 of catheter assembly 300and is in fluid communication with inflation lumen 322 formed withincatheter body 312 of catheter assembly 300. Balloon 320 includes balloonwall or membrane 330 which is selectively inflatable to dilate from acollapsed configuration to a desired and controlled expandedconfiguration. Balloon 320 can be selectively dilated (inflated) bysupplying a fluid into inflation lumen 322 at a predetermined rate ofpressure through inflation port 323. Balloon wall 330 is selectivelydeflatable, after inflation, to return to the collapsed configuration ora deflated profile. In one embodiment, balloon wall 330 can be definedby three sections, distal taper wall 332, medial working length 334, andproximal taper wall 336. In one embodiment, proximal taper wall 336 cantaper at any suitable angle θ, typically between about 10° to less thanabout 90°, when balloon 320 is in the expanded configuration.

Distal taper wall 332, medial working length 334, and proximal taperwall 336 of balloon wall 330 can be bound together by seams or be madeout of a single seamless material. Balloon 320 can be made from anysuitable material, including, but not limited to, polymers andcopolymers of polyolefins, polyamides, polyesters and the like. Thespecific material employed must be mutually compatible with the fluidsemployed in conjunction with balloon 320 and must be able to stand thepressures that are developed within balloon 320. Balloon wall 330 canhave any suitable thickness so long as the thickness does not compromiseproperties that are critical for achieving optimum performance. Suchproperties include high burst strength, low compliance, goodflexibility, high resistance to fatigue, the ability to fold, theability to cross and re-cross a desired region of treatment or anoccluded region in a lumen, and low susceptibility to defect caused byhandling. By way of example, and not limitation, the thickness can be inthe range of about 10 microns to about 30 microns, the diameter ofballoon 320 in the expanded configuration can be in the range of about 2millimeters (mm) to about 10 mm, and the length can be in the range ofabout 3 mm to about 40 mm, the specific specifications depending on theprocedure for which balloon 320 is to be used and the anatomy and sizeof the target lumen in which balloon 320 is to be inserted.

Balloon 320 may be dilated (inflated) by the introduction of a liquidinto inflation lumen 322. Liquids containing therapeutic and/ordiagnostic agents may also be used to inflate balloon 320. In oneembodiment, balloon 320 may be made of a material that is permeable tosuch therapeutic and/or diagnostic liquids. To inflate balloon 320, thefluid can be supplied into inflation lumen 322 at a predeterminedpressure, for example, between about one and 20 atmospheres.

Catheter assembly 300 also includes substance delivery assembly 338A andsubstance for injecting a treatment agent into a tissue of aphysiological passageway. In one embodiment, delivery assembly 338Aincludes needle 346A having a lumen with a diameter of, for example,0.004 inches (0.010 cm) to 0.012 inches (0.030 cm). Needle 346A ismovably disposed within delivery lumen 340A formed in catheter body 312.Delivery assembly 338B includes needle 346B movably disposed withindelivery lumen 340B formed in catheter body 312. Delivery lumen 340A anddelivery lumen 340B each extend between distal end 314 and proximal end313. Delivery lumen 340A and delivery lumen 340B can be made from anysuitable material, such as polymers and copolymers of polyamides,polyolefins, polyurethanes, and the like. Access to the proximal end ofdelivery lumen 340A or delivery lumen 340B for insertion of needle 346Aor 346B, respectively is provided through hub 351.

One or both of delivery lumen 340A and delivery lumen 340B may be usedto deliver a treatment agent to a treatment site (e.g., through needle346A and/or needle 346B). Alternatively, one delivery lumen (e.g.,delivery lumen 340A via needle 346A) may be used to deliver a treatmentagent (e.g., therapeutic angiogenic treatment agent) while the otherdelivery lumen (e.g., delivery lumen 340B via needle 346B) may be usedto deliver a therapeutic substance that is a non-therapeutic angiogenicsubstance.

Catheter assembly 300 also includes an imaging assembly. Suitableimaging assemblies include ultrasonic imaging assemblies, opticalimaging assemblies, such as an optical coherence tomography (OCT)assembly, magnetic resonance imaging (MRI). FIGS. 3-5 illustrate anembodiment of a catheter assembly, including an OCT imaging assembly.

OCT uses short coherence length light (typically with a coherent lengthof about 10 to 100 microns) to illuminate the object (e.g., blood vesselor blood vessel walls). Light reflected from a region of interest withinthe object is combined with a coherent reference beam. Interferenceoccurs between the two beams only when the reference beam and reflectivebeam have traveled the same distance. FIG. 8 shows one suitable OCTsetup similar in some respects to ones disclosed in U.S. Pat. Nos.5,465,147; 5,459,570; 5,321,501; 5,291,267; 5,365,325; and 5,202,745. Asuitable optical assembly for use in conjunction with a catheterassembly is made with fiber optic components that, in one embodiment,can be passed through the guidewire lumen (e.g., guidewire lumen 316 ofFIG. 3). Light having a relatively short coherence length, l_(c) (givenby l_(c)=C/Δf, where Δf is the spectral bandwidth) is produced by lightsource 380 (e.g., incandescent source, laser source or light emittingdiode of suitable wavelength) and travels through 50/50 coupler 382where it is divided into two paths. One path goes to blood vessel 383 tobe analyzed and the other path goes to a moveable reference mirror 385.The probe beam reflected from sample 383 and the reference beamreflected from reference mirror 385 are combined at coupler 382 and sentto detector 387. The optical path traversed by the reflected probe beamand the reference beam are matched to within one coherence length suchthat coherent interference can occur upon recombination at coupler 382.

Phase modulator 384 produces a temporal interference pattern (beats)when recombined with the reference beam. Detector 387 measures theamplitude of the beats. The amplitude of the detected interferencesignal is the measure of the amount of light scattered from within acoherence gate interval 388 inside, in this case, blood vessel 383 thatprovides equal path lengths for the probe and reference beams.Interference is produced only for light scattered from blood vessel 383which has traveled the same distance as light reflected from mirror 385.

In one embodiment, the optical fiber portion of the OCT imaging systemcan be inserted in the guidewire lumen of an over the wire catheter withguidewire lumen terminating at the imaging wire coupling. The body ofthe guidewire lumen (e.g., body of lumen 316 of the assembly of FIG. 3)and the body of the balloon assembly (e.g., body 330 of balloon assemblyin FIG. 3) should be transparent at the distal end to allow opticalimaging through the body of the lumen (e.g., through the body of balloon320). Thus, once the catheter assembly is placed, at a desired locationwithin, for example, a blood vessel, guidewire 318 may be removed andreplaced with an optical fiber. In a catheter assembly such asillustrated in FIG. 3, the replacement of the guidewire with an opticalfiber is done, in one embodiment, at low inflation pressure of balloon320.

Where an optical fiber is substituted for a guidewire, the dimensions ofa catheter does not have to be modified. Optical fibers having an outerdiameter of 0.014, 0.018, or 0.032 inches (0.36, 0.46, or 0.81 mm,respectively) are suitable for current guidewire lumens. Other imagingcomponents (e.g., fiber rotator, imaging screen, OCT system components,etc.) may be coupled to the optical fiber as it extends out hub 316 at aproximal end of the catheter assembly (e.g., at proximal end 313 ofcatheter assembly 300). Such components include, but are not limited to,a drive coupling that provides rotation and forward/reverse movement ofthe optical fiber; a detector, and an imaging screen.

FIG. 9 shows another embodiment of a catheter assembly including an OCTapparatus. In this embodiment, guidewire 3180 and optical fiber 3190“share” common imaging lumen 3160. Imaging lumen 3160 is preferably madeof a transparent material at the distal end utilized by optical fiber3190. Catheter assembly 3000 also includes balloon 3200 with needlelumens 3400A and 3400B coupled to a proximal portion of balloon 3200.

Referring to FIG. 9, guidewire 3180 exits imaging lumen 3160 at distaltip 3181 (i.e., distal to balloon 3200). Guidewire 3180 and opticalfiber 3190 are separated in imaging lumen 3160 by plug 3185 of, forexample, a polymer or copolymer material, having dimensions suitable tofill the lumen. Suitable polymers include polyimides, polyurethanes, andpolyolefins. A portion of plug 3185 may also serve as a ramp forguidewire exit port 3180. In this embodiment, imaging of a blood vessel(e.g., imaging of a wall of a blood vessel for thickness determination)is accomplished from a portion of imaging lumen corresponding with thelocation of balloon 3200. Thus, balloon 3200 is also preferably made ofa transparent material. Flush port 3187 may also be included forclearing imaging portion of imaging lumen 3160.

At a proximal end, imaging lumen 3160 of FIG. 9 terminates in drivecoupling 3195. Drive coupling 3195 provides rotation and forward/reversedirection movement of optical fiber 3190 and connection to the OCTsystem.

In another embodiment, the imaging assembly is based on ultrasonictechnology. Ultrasonic systems are referenced in U.S. Pat. Nos.4,794,931; 5,000,185; 5,049,130; 5,485,486; 5,827,313; and 5,957,941. Inone example, an ultrasonic imaging assembly, representatively includingan ultrasonic transducer, may be exchanged for a guidewire through aguidewire lumen such as described above with reference to the first OCTembodiment. In another embodiment, a guidewire and ultrasonic transducer“share” a common imaging lumen similar to the embodiment described withreference to FIG. 9 and the accompanying text. In either example,imaging of, for example, a blood vessel will take place through theballoon. In the case of ultrasonic imaging, the balloon and guidewirelumen need not be transparent.

FIGS. 6 and 7 are simplified sectional views of therapeutic substancedelivery assembly 338A in an undeployed and deployed arrangement,respectively. Delivery lumen 340A includes distal or first section 342and proximal or second section 344. Distal section 342 can includeoverhang section 347 that extends beyond opening 341 to provide a meansfor securing delivery lumen 340A to balloon 320. For example, overhangsection 347 can be adhered along the proximal taper wall 336 and workinglength 334 of balloon 320. In this manner, delivery lumen 340A iscontinually supported during, until, and after needle 346A is extendedfrom delivery lumen 340A. In one embodiment, as shown in FIG. 7,delivery lumen 340A includes bend region 350 at which distal section 342of delivery lumen 340A is capable of bending (or generally rotating)about pivotal point 351 with respect to proximal section 344. Forexample, to accomplish the pivotal movement, distal section 342 ofdelivery lumen 340A is in contact with proximal taper wall 336 ofballoon 320 (FIG. 3). Accordingly, in response to the inflation ofballoon 320, section 342 moves relative to section 344 to form bendregion 350. In one embodiment, section 342 can move from a substantiallylongitudinal position to a substantially perpendicular position. Thus,the angle θ of bend region 350 can vary between 0° and 90°. In oneexample, after inflation of balloon 320, angle θ can range from betweenabout 10° and 90°, for example, 45°.

Needle 346A is slidably or movably disposed in delivery lumen 340A.Needle 346A includes tissue-piercing tip 352 having dispensing port 353.Dispensing port 353 is in fluid communication with a lumen (not shown)of needle 346A. In one embodiment, the lumen of needle 346A can bepre-filled with a measured amount of a treatment agent. The lumen ofneedle 346A connects dispensing port 353 with treatment agent injectionport 359 (FIG. 3), which is configured to be coupled to varioussubstance dispensing means of the sort well known in the art, forexample, a syringe or fluid pump. Injection port 359 allows a measuredtreatment agent to be dispensed from dispensing port 353 as desired oron command.

Needle 346A is coupled at proximal end 313 of catheter assembly 310 in aneedle lock 355 (FIG. 3). Needle lock 355 can be used to secure needle346A in position once needle 346A has been either retracted and/orextended from delivery lumen 340A as described below. In one embodiment,an adjustment knob 357 can be used to set the puncture distance ofneedle 346A as it is extended out from delivery lumen 340A and into thewall of the physiological lumen. For example, adjustment knob 357 mayhave calibrations, such that each revolution of the adjustment knob fromone calibrated mark to another represents a fixed distance of travel forneedle 346A. The portion of needle 346A protruding from delivery lumen340 can be of any predetermined length, the specific length beingdependent upon the desired depth of calibrated penetration and theprocedure for which delivery assembly 338A is to be used. The protrudinglength of needle 346A can be from about 250 microns to about fourcentimeters (cm). It is appreciated that other mechanisms for securingneedle 346A at a retracted or extended position may alternatively beused, including the incorporation of a mechanical stop optionallyincluding a signaling (e.g., electrical signaling) device as describedin commonly-owned U.S. patent application Ser. No. 09/746,498 (filedDec. 21, 2000), titled “Directional Needle Injection Drug DeliveryDevice”, and incorporated herein by reference.

Needle 346A is slidably disposed in delivery lumen 340A, so that it canmove between a first retracted position (FIG. 6) and a second extendedposition (FIG. 7). In its first or retracted position, tissue-piercingtip 352 is located inboard of the distal surface of catheter body 312,so as to avoid damaging tissue during deployment of catheter assembly310. In its second or extended position, tissue-piercing tip 352 islocated outboard of the distal surface of catheter body 312, so as topermit needle tip 352 to penetrate the tissue surrounding thephysiological passageway in which catheter assembly 310 is disposed.

Referring again to FIGS. 6 and 7, deflector 360 is disposed along aninner wall 362 of delivery lumen 340A. In one embodiment, deflector 360includes distal section 370, medial section 372 and proximal section374. In one embodiment, distal section 370 can be supported by deliverylumen 340A by bonding distal section 370 to overhang section 347 ofdelivery lumen 340A. Medial section 372 of deflector 360 can be disposedon inner wall 362 of delivery lumen 340A, such that as delivery lumensection 342 rotates relative to delivery section 344 to form bend region350, deflector 360 is positioned over the outside of the curvature ofbend region 350. Proximal section 374 exits out of delivery lumen 340Aand is adhered to an outside wall 378 of delivery lumen 340A using anadhesive, such as glue or the like.

Deflector 360 can be any device that will provide a shield to protectthe wall of delivery lumen 340A while being small enough, such thatdeflector 360 does not impact the track of catheter assembly 310 in anysignificant manner. In one embodiment, deflector 360 can be a ribbonmember. The ribbon member can be made thin, flexible and resilient suchthat the ribbon member can move and bend as delivery lumen sections 342and 344 bend and move relative to each other. Positioning deflector 360of a ribbon member on the outside of the curvature of bend region 350allows deflector 360 to shield the delivery lumen wall from piercing andthe like by needle 346A as needle 346A moves through bend region 350.Deflector 360 also provides a surface upon which needle 346A can be madeto track through bend region 350.

Deflector 360 is sized to fit into and along inner wall 362 of deliverylumen 340A without occluding or interfering with the ability of needle346A to translate through bend region 350. For example, deflector 360can have a thickness of between about 0.0005 inches (0.127 mm) and about0.003 inches (0.762 mm). The width of deflector 360 may be between about0.005 inches (1.27 mm) and about 0.015 inches (3.81 mm). The length ofdeflector 360 may be between about 1 cm and about 10 cm. Deflector 360can be made from any suitable material, which allows deflector 360 tofunction, such as stainless steel, platinum, aluminum and similar alloymaterials with similar material properties. In one embodiment, deflector360 can be made from super-elastic alloys, such as nickel titaniumalloys, for example NiTi.

The catheter assembly described with reference to FIG. 3 or FIG. 9 maybe used to introduce a treatment agent such as described above at adesired location. FIG. 10 illustrates one technique. FIG. 11 presents ablock diagram of one technique. With reference to FIGS. 10 and 11, in aone procedure, guidewire 318 is introduced into, for example, arterialsystem of the patient (e.g., through the femoral artery) until thedistal end of guidewire 318 is upstream of the narrowed lumen of theblood vessel (e.g., upstream of occlusion 185). Catheter assembly 300 ismounted on the proximal end of guidewire 318 and advanced over theguidewire 318 until catheter assembly 300 is position as desired. In theexample shown in FIG. 10, catheter assembly 310 is positioned so thatballoon 320 and delivery lumen 340 a are upstream of the narrowed lumenof LCX 170 (block 410). Angiographic or fluoroscopic techniques may beused to place catheter assembly 300. Once balloon 320 is placed andsubject to low inflation pressure, guidewire 318 is removed and replacedin one embodiment with an optical fiber. In the catheter assembly shownin FIG. 9, the imaging portion of an imaging device (e.g., OCT,ultrasonic, etc.) may be within the imaging lumen as the catheter ispositioned. Once positioned, in this case upstream of occlusion 185, theimaging assembly is utilized to view the blood vessel and identify thevarious layers of the blood vessel (block 420).

The imaging assembly provides viewable information about the thicknessor boundary of the intimal layer 110, media layer 120, and adventitiallayer 130 of LCX 170 (See FIG. 1). The imaging assembly may also be usedto measure a thickness of a portion of the blood vessel wall at thelocation, e.g., the thickness of the various layers of LCX 170.

LCX 170 is viewed and the layer boundary is identified or a thickness ofa portion of the blood vessel wall is imaged (and possibly measured),(block 140). The treatment site may be identified based on the imaging(and possibly measuring). In one example, the treatment site is aperi-adventitial site (e.g., site 190) adjacent to LCX 170. At thispoint, balloon 320 is dilated as shown in FIG. 7 by, for example,delivering a liquid or gas to balloon 320 through inflation lumen 322.The inflation of balloon 320 causes needle lumen 338 to move proximateto or contact the blood vessel wall adjacent to the treatment site.Needle 346A is then advanced a distance into the wall of the bloodvessel (block 140). A real time image may be used to advance needle346A. Alternatively, the advancement may be based on a measurement ofthe blood vessel wall or layer boundary derived from an optical image.

In the embodiment shown in FIG. 10, needle 346A is advanced through thewall of LCX 170 to peri-adventitial site 190. Needle 346A is placed at asafe distance, determined by the measurement of a thickness of the bloodvessel wall and the proximity of the exit of delivery lumen 340A to theblood vessel wall. Adjustment knob 357 may be used to accurately locateneedle tip 346A in the desired peri-adventitial region. Once inposition, a treatment agent, such as a treatment agent is introducedthrough needle 346A to the treatment site (e.g., peri-adventitial site190).

In the above described embodiment of locating a treatment agent withinor beyond a blood vessel wall (e.g., at a peri-adventitial site), it isappreciated that an opening is made in or through the blood vessel. Insame instances, it may be desirable to plug or fill the openingfollowing delivery of the treatment agent. This may be accomplished byintroduction through a catheter lumen of cyanoacrylate or similarmaterial that will harden on contact with blood.

In the above embodiment, an illustration and method was described tointroduce a treatment agent at a peri-adventitial site. It isappreciated that the treatment agent may be introduced to a portion ofthe wall of the blood vessel. In another embodiment, the introduction isat a point beyond the media layer (e.g., beyond media layer 120 inFIG. 1) to the adventitial layer (e.g., adventitial layer 130 in FIG.1). Further, the techniques and treatment agents described may furtherbe used to introduce a treatment agent directly into the tissue of themyocardium.

In the preceding detailed description, the invention is described withreference to specific embodiments thereof. It will, however, be evidentthat various modifications and changes may be made thereto withoutdeparting from the broader spirit and scope of the invention as setforth in the claims. The specification and drawings are, accordingly, tobe regarded in an illustrative rather than a restrictive sense.

What is claimed is:
 1. A method comprising: positioning a distal portionof a delivery device at a location in a blood vessel the distal portionof the delivery device comprising a balloon and a delivery lumen coupledto an exterior surface of the balloon; imaging a thickness of at least aportion of a wall of the blood vessel at the location with an imagingassembly disposed in a second lumen of the delivery device; identifyinga treatment site beyond an external elastic lamina of the blood vesselbased on the imaging; inflating the balloon to cause a portion of thedelivery lumen to pivot from a first position toward a direction of thewall of the blood vessel; after inflating the balloon to pivot thedelivery lumen, advancing a needle beyond the delivery lumen of thedelivery device a distance into the wall of the blood vessel to thetreatment site beyond the external elastic lamina of the blood vessel;and after advancing the needle, introducing a treatment agent in asustained release composition through the needle.
 2. The method of claim1, wherein imaging comprises ultrasonic imaging the portion of the bloodvessel wall.
 3. The method of claim 1, wherein imaging comprises opticalimaging the portion of the blood vessel wall.
 4. The method of claim 1,wherein the treatment site comprises a peri-adventitial space.
 5. Themethod of claim 1, wherein the treatment site comprises a site radiallyoutward from a peri-adventitial space.
 6. The method of claim 1, whereinpositioning the distal portion of the delivery device comprisespositioning a distal opening of the delivery lumen at a positionupstream from an obstruction.
 7. The method of claim 1, wherein theblood vessel is part of a network and another blood vessel in thenetwork other than the blood vessel wherein the delivery device ispositioned comprises an obstruction.
 8. The method of claim 1, whereinthe sustained release composition comprises a carrier.
 9. The method ofclaim 8, wherein the carrier comprises particles having an averagediameter of 10 microns or less.
 10. The method of claim 8, wherein thecarrier includes an opsonin-inhibitor.
 11. The method of claim 1,wherein the treatment agent comprises an agent that induces aninflammation-inducing response.
 12. The method of claim 11, wherein thetreatment agent comprises a thermally conductive material, and themethod further comprises, following introducing the treatment agent,heating the treatment agent.
 13. The method of claim 1, wherein thetreatment agent comprises an agent directed to a specific binding site,and wherein the treatment agent is operable to stimulate angiogenesis.14. The method of claim 1, wherein imaging the thickness comprisesimaging the thickness with optical coherence tomography.
 15. The methodof claim 1, wherein the imaging comprises imaging through the balloon.16. The method of claim 15, wherein the imaging through the ballooncomprises imaging through a transparent material of the balloon.
 17. Themethod of claim 1, wherein the treatment agent comprises a non-specifictreatment agent operable to induce inflammation.
 18. The method of claim1, wherein the treatment agent comprises at least one selected from solgel particles, calcium phosphate glass comprising iron, fibrin, gelatin,low molecular weight hyaluronic acid, chitin, bacterial polysaccharides,and metal particles.
 19. The method of claim 1, further comprisingdeflecting the needle with a ribbon member deflector.
 20. The method ofclaim 1, further comprising: measuring the thickness of the portion ofthe wall of the blood vessel using the imaging assembly; and identifyingthe treatment site based on the imaging and measuring.
 21. A methodcomprising: positioning a distal portion of a delivery device at alocation in a blood vessel the distal portion of the delivery devicecoupled to an exterior surface of a balloon; imaging a thickness of atleast a portion of a wall of the blood vessel at the location with animaging assembly disposed in a lumen of the delivery device; pivotingthe distal portion of the delivery device from a first position towardthe portion of the wall of the blood vessel by inflating the balloon;after pivoting the distal portion of the delivery device, advancing aneedle beyond the distal portion of the delivery device a distance intothe wall of the blood vessel to a treatment site beyond an externalelastic lamina of the blood vessel; and after advancing the needle,introducing a treatment agent through the needle, wherein the treatmentagent comprises an inflammation-inducing agent.
 22. The method of claim21, wherein the treatment agent comprises an agent directed to specificbinding sites that is operable to stimulate angiogenesis.
 23. The methodof claim 21, wherein the treatment agent comprises carrier particlesincluding the inflammation-inducing agent and having a sustained-releaseproperty within a physiological setting.
 24. The method of claim 21,wherein the inflammation-inducing agent comprises at least one of asol-gel particle, a silica particle, a glass including iron, chitin,fibrin, bacterial polysaccharides, vaccines, and particles of metal. 25.The method of claim 21, wherein the inflammation-inducing agentcomprises at least one of a polycaprolactone, apolyhydroxybutyrate-valerate, a poly(oxy)ethylene, a polyurethane, and asilicone.
 26. The method of claim 21, wherein the treatment agentcomprises carrier particles including the inflammation-inducing agent,and wherein the carrier particles comprise at least one selected frompoly (L-lactide), poly (D,L-lactide), poly (glycolide), poly(lactide-co-glycolide), polycaprolactone, polyanhydride, polydiaxanone,polyorthoester, polyamino acids, poly (trimethylene carbonate), andcombinations thereof.
 27. The method of claim 21, wherein the imagingcomprises imaging through the balloon disposed at the distal portion ofthe delivery device.
 28. The method of claim 27, wherein the imagingthrough the balloon comprises imaging through a transparent material ofthe balloon.
 29. The method of claim 21, wherein the treatment agentcomprises a non-specific treatment agent.
 30. The method of claim 21,wherein the treatment agent comprises at least one selected from sol gelparticles, calcium phosphate glass having iron, fibrin, gelatin, lowmolecular weight hyaluronic acid, chitin, bacterial polysaccharides, andmetal particles.
 31. The method of claim 21, further comprisingdeflecting the needle with a ribbon member deflector.
 32. The method ofclaim 21, wherein the imaging comprises imaging with optical coherencetomography.